There have been a number of proposed links between the immune system and the nervous system (and possible interactions with the reproductive system) including the prolonged post-natal development/maturation of both systems and with infection in the pregnant mother the possible transfer of factors of the pro-inflammatory cascade (TNFalpha, Interleukin-6) to the offspring and long-term effects on the child as related to an immune-mediated response. Local activation of inflammatory cells in the brain may contribute to neuronal death that occurs following acute brain injury as well as more progressive degenerative processes. In this network, various cells communicate and regulate complex processes of initiation, propagation, and suppression of immune and inflammatory responses. As a host defense response it serves to protect the brain however, when the response becomes dysregulated this can lead to adverse events. Under this framework we have reported that microglia cells are critical not only in the initial phase of the damage response but also in the repair process following injury.We have demonstrated that apoptosis in neurons can be initiated by the activation of either of the receptors for tumor necrosis factor and that the fate of neurons within a high inflammatory environment is associated with the surrounding resident immune cell, the microglia (Harry et al., 2007). We have more recently reported an tightly regulated interaction between both of the TNF receptors in signalling for neuronal death. [unreadable] The purpose of this project is to identify the critical features of the glia response that may either cause or exacerbate an ongoing process of neuronal death and how these features change with chemical exposure, head trauma and stress as well as the immune system integrity, and life stage. These features include not only the individual cell response but also the extracellular environment that may influence the outcome of such responses. Thus, it is the purpose of this project to attempt to identify interactions between the physical and the central immune systems that may contribute not only to acute adverse effects but also to long-term adverse outcomes. Understanding the link between the resident immune cells of the brain, the systemic immune system, manifestation of neurodegenerative disease, and the ability/inability to mount a regenerative response will provide a critical step toward identifying approaches to treat such conditions. Using genetically modified mice we are able to address questions with regards to genetic susceptibility for disease processes as well as specific modifications of the immune system and inflammatory response to injury. In addition to the impact of the immune cells on neuronal death, we are currently examining the role of neuroinflammation in the initiation and success of injury-induced adult neurogenesis and how this process may be altered as a function of age or environmental exposure.